Depression is the leading cause of disease-related disability in women. Studies have shown that the lifetime prevalence of a major depressive disorder in women (21,3%) is almost twice that in men (12.7%). An altered stress response resulting in intermittent aberrant cortisol exposure often accompanies depression and anxiety disorders. Growing evidence indicates that this phenotype may precede the manifestations of affective illness and persist even when the mental disorder has been in long term remission. It has been proposed that aberrant cortisol dynamics is an intermediate phenotype placing individuals at increased risk for the development of certain psychiatric disorders. In aim 1, we are proposing to perform a quantitative trait study testing for an association of a specific phenotype with a set of 15 candidate genes and functional polymorphisms in a population of healthy women. We will determine Which functional polymorphisms and gene haplotypes predict the magnitude of cortisol responses to psychological stress. We selected ~20 SNPs per gene that had minor allelic frequencies of >10%, and based on data from HAPMAP (International HAPMAP consortium, 2003), captured the common variation within the haplotype blocks across each gene. In aim 2, we propose to examine the relationship of cortisol responses to personality traits, with the hypothesis that those personalities most closely related to depression and anxiety disorders will be most correlated with heightened stress response. This hypothesis is supported by our preliminary data showing a significant correlation between cortisol responses to the psychological stress test and the personality dimensions of Neuroticism. There is growing interest in neuroticism as a risk factor for depression. In aim 3, will take the associated genetic variants discovered in aim 1 and test them on a separate, already existing sample, using the cortisol-correlated personality traits from specific aim 2. The existing sample, the Epidemiologic Catchment Area Genetics of Personality Sample contains 350 women who have NEO and TCI scores previously obtained, and DNA samples available. Results from these studies will inform the mental health field as well as the broader disciplines of neuroscience and metabolism.